Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer""s disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
A brief description of the potential utility of cyclooxygenase-2 inhibitors is given in an article by John Vane, Nature, Vol. 367, pp. 215-216, 1994, and in an article in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994.
The invention encompasses the novel compounds of Formula I, which are useful in the treatment of cyclooxygenase-2 mediated diseases: 
or a pharmaceutically acceptable salt thereof wherein:
X is selected from the group consisting of:
(a) a bond,
(b) xe2x80x94(CH2)mxe2x80x94, wherein m=1 or 2,
(c) xe2x80x94C(O)xe2x80x94,
(d) xe2x80x94Oxe2x80x94,
(e) xe2x80x94Sxe2x80x94, and
(f) xe2x80x94N(R5)xe2x80x94;
R1 is selected from the group consisting of:
(a) C1-10alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-10alkoxy,
(4) C1-10alkylthio, and
(5) CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or
xe2x80x83a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms,
wherein groups (b) and (c) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C1-10alkoxy,
(3) C1-10alkylthio,
(4) CN,
(5) C1-10alkyl, optionally substituted to its maximum with halo, and
(6) N3;
R2 is selected from the group consisting of
(a) C1-6alkyl, optionally substituted to its maximum with halo,
(b) NH2, and
(c) NHC(O)C1-10alkyl, optionally substituted to its maximum with halo;
R3 and R4 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo, and
(c) C1-6alkyl, optionally substituted to its maximum with halo; and
R5 is selected from the group consisting of:
(a) hydrogen and
(b) C1-6alkyl, optionally substituted to its maximum with halo.
The invention also encompasses certain pharmaceutical compositions comprising compounds of Formula I as well as methods of treating cyclooxygenase-2 mediated diseases comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of Formula I.
The invention encompasses the novel compounds of Formula I, which are useful in the treatment of cyclooxygenase-2 mediated diseases 
or a pharmaceutically acceptable salt thereof wherein:
X is selected from the group consisting of:
(a) a bond,
(b) xe2x80x94(CH2)mxe2x80x94, wherein m=1 or 2,
(c) xe2x80x94C(O)xe2x80x94,
(d) xe2x80x94Oxe2x80x94,
(e) xe2x80x94Sxe2x80x94, and
(f) xe2x80x94N(R5)xe2x80x94;
R1 is selected from the group consisting of:
(a) C1-10alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-10alkoxy,
(4) C1-10alkylthio, and
(5) CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or
xe2x80x83a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms,
wherein groups (b) and (c) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C1-10alkoxy,
(3) C1-10alkylthio,
(4) CN,
(5) C1-10alkyl, optionally substituted to its maximum with halo, and
(6) N3;
R2 is selected from the group consisting of
(a) C1-6alkyl, optionally substituted to its maximum with halo,
(b) NH2, and
(c) NHC(O)C1-10alkyl, optionally substituted to its maximum with halo;
R3 and R4 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo, and
(c) C1-6alkyl, optionally substituted to its maximum with halo; and
R5 is selected from the group consisting of:
(a) hydrogen and
(b) C1-6alkyl, optionally substituted to its maximum with halo.
An embodiment of the invention is that wherein X is a bond.
Another embodiment of the invention is that wherein X is xe2x80x94Oxe2x80x94.
Another embodiment of the invention is that wherein X is xe2x80x94Sxe2x80x94.
Another embodiment of the invention is that wherein R2 is CH3.
Another embodiment of the invention is that wherein R3 is hydrogen.
Another embodiment of the invention is that wherein m is 1.
Another embodiment of the invention encompasses compounds of Formula I wherein R1 is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C1-10alkoxy,
(3) C1-10alkylthio,
(4) CN,
(5) C1-10alkyl, optionally substituted to its maximum with halo, and
(6) N3.
A class of this embodiment encompasses compounds wherein R1 is as defined above and R2 is CH3. Another class of this embodiment encompasses compounds wherein R1 is as defined above and R3 is H.
Another embodiment of the invention encompasses compounds of Formula I wherein R1 is heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms, wherein heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C1-10alkoxy,
(3) C1-10alkylthio,
(4) CN,
(5) C1-10alkyl, optionally substituted to its maximum with halo, and
(6) N3.
Another embodiment of the invention encompasses compounds of Formula I wherein R1 is pyridyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C1-10alkoxy,
(3) C1-10alkylthio,
(4) CN,
(5) C1-10alkyl, optionally substituted to its maximum with halo, and
(6) N3.
Another embodiment of the invention encompasses compounds of Formula I wherein R1 is C1-6alkyl, optionally substituted with hydroxy.
In another aspect, the invention encompasses a pharmaceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.
In another aspect, the invention encompasses a method of treating or preventing an inflammatory disease in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound of Formula I in an amount effective to treat or prevent said inflammatory disease.
In another aspect, the invention encompasses a method of treating or preventing a cyclooxygenase-2 mediated disease advantageously treated by an active agent that selectively inhibits cyclooxygenase-2 in preference to cyclooxygenase-1 in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound of Formula I in an amount effective to treat or prevent said cyclooxygenase-2 mediated disease.
In another aspect, the invention encompasses the use of a compound of Formula I in the manufacture of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
The invention is illustrated by the compounds of the Examples disclosed herein as well as the compounds of Table I.
For purposes of this specification, the following abbreviations have the indicated meanings:
For purposes of this specification, xe2x80x9calkylxe2x80x9d means linear branched and cyclic structures, and combinations thereof, containing the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl- 4-propylnonyl, cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl and the like.
For purposes of this specification, xe2x80x9calkoxyxe2x80x9d means alkoxy groups of the indicated number of carbon atoms of a straight, branched, or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
For purposes of this specification, xe2x80x9calkylthioxe2x80x9d means alkylthio groups of the indicated number of carbon atoms of a straight, branched or cyclic configuration. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies xe2x80x94SCH2CH2CH3.
For purposes of this specification xe2x80x9chaloxe2x80x9d means F, Cl, Br, or I.
Exemplifying the invention are the following compounds:
(1) 4-(4-Methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
(2) 3-(4-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
(3) 3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
(4) 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
(5) 6-Difluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
(6) 6-Fluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
(7) 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenylthio-pyran-2-one,
(8) 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenoxy-pyran-2-one,
(9) 6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyridin-3-yl-pyran-2-one,
(10) 3-Isopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
(11) 4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one,
(12) 3-Isopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one,
(13) 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and
(14) 3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like, and basic ion exchange resins.
It will be understood that in the discussion of methods of treatment that follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The compounds of Formula I are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. The compounds of Formula I may also be of use in the treatment and/or prevention of cyclooxygenase-mediated proliferative disorders such as may occur in diabetic retinopathy and tumour angiogenesis.
The compounds of Formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer""s disease, and for the prevention of bone loss (treatment of osteoporosis) and for the treatment of glaucoma.
By virtue of its high cyclooxygenase-2 (COX-2) activity and/or its specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), The compounds of Formula I are useful as alternatives to conventional non-steroidal antiinflammatory drugs (NSAID""S), particularly where such non-steroidal antiinflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; and those prior to surgery or taking anticoagulants.
Similarly, the compounds of Formula I are useful as a partial or complete substitute for conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of a compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a prostaglandin including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
For the treatment of any of these cyclooxygenase mediated diseases, the compounds of Formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
As indicated above, pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxy-ethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the present invention can be prepared according to the following methods:
Method A
An appropriately 3-substituted 5-hydroxy-4-(4-methylsulfonyl)phenyl-5H-furan-2-one II (WO 9636623) is reacted with a ylide, generated from the reaction of (methoxymethyl)triphenylphosphonium chloride with a base such as potassium t-butoxide in a solvent such as THF to give a penta-2,4-dienoic acid intermediate III. Subsequently refluxing in a solvent such as toluene with an acidic catalyst such as p-toluenesulfonic acid affords pyrone IV. 
Method B
4-Bromthioanisole is reacted with an alk-1-yn-3-ol in the presence of a palladium (0) catalyst, catalytic amount of a copper (1) salt such as CuI, catalytic amount of triphenylphosphine and a base such as triethylamine in a solvent such as CH3CN to give the alkyn-ol intermediate V. Oxidation with an oxidant such as MnO2 provides ketone VI, which is reacted with diethyl malonate in the presence of a base such as activated barium hydroxide in an alcoholic solvent such as ethanol to give the pyrone intermediate VII. Hydrolysis of the ester with a base such as aqueous sodium hydroxide and followed by decarboxylation with copper bronze in quinoline affords intermediate VIII. Bromination of VIII in a solvent such as CH2Cl2 gives IX. Coulping with IX with an appropriately boronic acid in the presence of a palladium (0) catalyst and a base such as sodium carbonate, and subsequently oxidation with an oxidant such as mCPBA affords pyrone X. 
Method C
Sufide IX is oxidized with an oxidant such as mCPBA to give sulfone XI, which is subsequently reacted with an appropriate nucleophile in the presence of an alkaline base such as NaOH or in the presence of an alkaline base such as K2CO3 with CuO to give pyrone I. 
Method D
tert-Butyl acetoacetate is treated with sodium hydride followed by n-butyllithium and the resulting dianion is reacted with an ester to provide a diketo ester intermeidate XII. Treatment with trifluoroacetic acid gives an acid intermediate, which is stirred with acetic anhydride to furnish an acetylated pyran-2-one intermediate. Subsequent hydrolysis with an aqueous alkaline base such as sodium hydroxide affords the hydroxyl pyran-2-one intermediate XII. Reaction with trifluoromethanesulfonic anhydride yields a triflate intermediate, which is coupled with 4-(methylthio)phenylboronic acid in the presence of a Pd (0) catalyst and a base such as sodium carbonate gives intermediate VIII. This intermediate VIII is then further converted to pyrone X as described in Method B. 
Method E
Pyrone XIV, obtained from pyrone intermediate IX with an appropriate coupling reaction such as Suzuki reaction as described in Method D, is oxidized with selenium dioxide to give an aldehyde intermediate XV. Treatment with diethylaminosulfur trifluoride followed by oxidation with an oxidant such as mCPBA affords pyrone XVI. 
Method F
Pyrone XV obtained from Method E is reduced with a reducing agent such as sodium borohydride to give alcohol XVII. Treatment with diethylaminosulfur trifluoride followed by oxidation with an oxidant such as mCPBA affords pyrone XVIII. 
Method G
trimethyl(trifluoromethyl)silane in the presence of a fluoride ion such as tetrabutylammonium fluoride to give the trifluoromethanol intermediate XIX. Treatment with phenyl chlorothionoformate in the presence of DMAP in a solvent such as acetonitrile affords thiocarbonate intermediate XX. Radical deoxygenation with tributyltin hydride generated in situ from tributyltin chloride with sodium borohydride yields XXI. Subsequent oxidation with an oxidant such as mCPBA gives the desired pyrone XXII. 
Method H
Pyrone IX obtained from Method B is coupled with 2-methyl-3-butyn-2-ol in the presence of Cu (I) and Pd (II) catalysts to provide the intermediate XXIII. Pyrone XXIII is then oxidized with an oxidant such as MMPP and followed by hydrogenation to give the desired pyrone XXV. 
Representative Compounds
Tables I illustrates novel compounds of the present invention.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25xc2x0 C.;
(ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60xc2x0 C.;
(iii) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only;
(iv) melting points are uncorrected and xe2x80x98dxe2x80x99 indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
(v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data;
(vi) yields are given for illustration only;
(vii) when given, NMR data is in the form of delta (?) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition xe2x80x9cArxe2x80x9d signifies an aromatic signal;
(viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), M.P. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).